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PXD047837

PXD047837 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleATM Inhibition Exploits Checkpoint Defects and ATM-Dependent Double Strand Break Repair in TP53-Mutant Glioblastoma
DescriptionDetermining the balance between DNA double strand break repair (DSBR) pathways is essential for understanding treatment response in cancer. We report a novel method for simultaneously measuring non-homologous end joining (NHEJ), homologous recombination (HR), and microhomology-mediated end joining (MMEJ). This approach revealed enhanced MMEJ and HR in glioblastoma (GBM) xenograft models with acquired temozolomide (TMZ) resistance. Knockdown of proteins in either pathway enhanced killing by TMZ, and a targeted screen identified pharmacological-grade dual HR/MMEJ inhibitors, including AZD1390, an ATM kinase inhibitor. AZD1390 suppressed DSB end resection, blocked phosphorylation of end protection proteins in response to DNA damage, and potentiated TMZ in treatment-naïve and treatment-resistant models. TP53-mutant GBMs were most susceptible to AZD1390 in combination with DNA-damaging agents due to elevated ATM-dependent HR/MMEJ, preferential activation of these pathways in response to DNA damage, and a defective G2/M checkpoint, which caused these GBMs to enter mitosis despite unrepaired DNA damage, leading to cell death via apoptosis. This report establishes ATM-dependent HR and MMEJ as targetable resistance mechanisms in TP53-mutant GBM and establishes an approach for simultaneously measuring multiple DSBR pathways in treatment selection and oncology research.
HostingRepositoryPRIDE
AnnounceDate2024-10-22
AnnouncementXMLSubmission_2024-10-22_06:32:41.355.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterGary Bradshaw
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListphosphorylated residue; iodoacetamide derivatized residue
InstrumentOrbitrap Fusion Lumos
Dataset History
RevisionDatetimeStatusChangeLog Entry
02023-12-14 11:57:38ID requested
12024-03-08 10:47:38announced
22024-10-22 06:32:41announced2024-10-22: Updated project metadata.
Publication List
Dataset with its publication pending
Keyword List
submitter keyword: DNA double strand break repair,TP53-Mutant Glioblastoma, ATM Inhibition
Contact List
Zachary D. Nagel
contact affiliation1. Harvard T.H. Chan School of Public Health, Boston, MA 02115
contact emailznagel@hsph.harvard.edu
lab head
Gary Bradshaw
contact affiliationHarvard Medical School
contact emailGary_bradshaw@hms.harvard.edu
dataset submitter
Full Dataset Link List
Dataset FTP location
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PRIDE project URI
Repository Record List
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